Isoxazole derivatives to be used as phosphodiesterase VII inhibitors

ABSTRACT

The invention relates to compounds of formula I and to their physiologically acceptable salts and solvates which act as phosphodiesterse VII inhibitors and are thus useful for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases, rheumatoid arthritis, multiple sclerosis, Crohn&#39;s disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumor growth, tumor metastases, sepsis, memory disturbances, atherosclerosis and AIDS.

This application is a 371 of PCT/EP00/10239 filed Oct. 18, 2000.

The invention relates to compounds of formula I

in which

R¹, R², R³, R⁴ are each, independently of one another, Hal, OA¹, SA¹, A,H, COOA¹, CN or CONA¹A²,

R⁵ is COOA¹, CN or CONA¹A²,

A¹, A² are each, independently of one another, H, A, alkenyl, cycloalkylor alkylenecycloalkyl,

A is alkyl having 1 to 10 C atoms,

Hal is F, Cl, Br or I,

and their physiologically acceptable salts and/or solvates asphosphodiesterase VII inhibitors.

The invention further relates to the use of the compounds of the formulaI for producing a pharmaceutical for controlling allergic disorders,asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skindisorders, inflammatory disorders, autoimmune diseases such as, forexample, rheumatoid arthritis, multiple sclerosis, Crohn's disease,diabetes mellitus or ulcerative colitis, osteoporosis, transplantrejection reactions, cachexia, tumour growth or tumour metastases,sepsis, memory disturbances, atherosclerosis and AIDS.

Compounds of the formula I are described by Bionet.

The invention was based on the object of finding novel compounds withvaluable properties, in particular those which can be used for producingpharmaceuticals.

It has been found that the compounds of the formula I and their saltshave very valuable pharmacological properties while being welltolerated. In particular, they show a specific inhibition of the“rolipram-insensitive” cAMP phosphodiesterase (PDE VII).

The biological activity of the compounds of the formula I can bedetermined by methods like those described, for example, by M. A.Giembycz et al. in Br. J. Pharmacol. (1996), 118, 1945-1958. Theaffinity of the compounds for cAMP phosphodiesterase (PDE VII) isdetermined by measuring their IC₅₀ values (concentration of theinhibitor required to achieve 50% inhibition of the enzymic activity).The determinations were carried out using homogenized SK-N-SHneuroblastoma cells in place of T lymphocytes, and CI-930 was employedto inhibit PDE III. The latter is a selective PDE III inhibitor (J. A.Bristol et al., J. Med. Chem. 1984, 27(9), 1099-1101).

The compounds of the formula I can be employed for treating asthmaticdisorders. The antiasthmatic effect can be determined, for example, inanalogy to the method of T. Olsson, Acta allergologica 26, 438-447(1971).

Since cAMP inhibits osteoclastic cells and stimulates osteoblastic cells(S. Kasugai et al., M 681 and K. Miyamoto, M 682, in Abstracts of theAmerican Society for Bone and Mineral Research 18th Annual Meeting,1996), the compounds of the formula I can be employed for treatingosteoporosis.

The compounds additionally show an antagonistic effect on the productionof TNFα (tumour necrosis factor) and are therefore suitable for treatingallergic and inflammatory disorders, autoimmune diseases such as, forexample, rheumatoid arthritis, multiple sclerosis, Crohn's disease,diabetes mellitus or ulcerative colitis, transplant rejection reactions,cachexia and sepsis.

The antiinflammatory effect of the substances of the formula I and theirefficacy for the treatment of, for example, autoimmune diseases such asmultiple sclerosis or rheumatoid arthritis can be determined in analogyto the methods of N. Sommer et al., Nature Medicine 1, 244-248 (1995) orL. Sekut et al., Clin. Exp. Immunol. 100, 126-132 (1995).

The compounds can be employed for treating cachexia. The anti-cachecticeffect can be tested in TNF-dependent models of cachexia (P. Costelli etal., J. Clin. Invest. 95, 2367ff. (1995); J. M. Argiles et al., Med.Res. Rev. 17, 477ff. (1997)).

The PDE VII inhibitors are also able to inhibit the growth of tumourcells and are therefore suitable for tumour therapy (for PDE IVinhibitors, cf. D. Marko et al., Cell Biochem. Biophys. 28, 75ff.(1998)).

They can furthermore be employed for the therapy of sepsis and fortreating memory disturbances, atherosclerosis, atopic dermatitis andAIDS, and for treating T-cell-dependent diseases (L. Li et al., Science,1999, 283, 848-851).

The invention further relates to the use of phosphodiesterase VIIinhibitors for producing a pharmaceutical for controlling allergicdisorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis andother skin disorders, inflammatory disorders, autoimmune diseases suchas, for example, rheumatoid arthritis, multiple sclerosis, Crohn'sdisease, diabetes mellitus or ulcerative colitis, osteoporosis,transplant rejection reactions, cachexia, tumour growth or tumourmetastases, sepsis, memory disturbances, atherosclerosis and AIDS.

The compounds of the formula I can be employed as active pharmaceuticalingredients for inhibiting PDE VII in human and veterinary medicine.

A is alkyl having 1-10 C atoms and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Catoms and is preferably methyl, ethyl or propyl, also preferablyisopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but is alson-pentyl, neopentyl, isopentyl or hexyl. It is also possible for 1-7 Hatoms in the radicals to be replaced by F and/or Cl. A is thereforealso, for example, trifluoromethyl or pentafluoroethyl.

Cycloalkyl has 3-9 C atoms and is preferably, for example, cyclopentylor cyclohexyl. Alkenyl has 2-10 C atoms, is linear or branched and ispreferably vinyl, propenyl or butenyl.

Alkylenecycloalkyl has 4-10 C atoms and is, for examplemethylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl orethylenecyclohexyl.

Accordingly, the invention relates in particular to those compounds ofthe formula I as phosphodiesterase VII inhibitors in which at least oneof the said radicals has one of the preferred meanings indicated above.Some preferred groups of compounds can be expressed by the followingpart-formulae Ia to Ig which correspond to formula I and in which theundefined radicals have the meaning stated for formula I, but in which

in Ia

R¹ is H;

in Ib

R¹ and R² are H;

in Ic

R¹ is H and

R² is F or Cl;

in Id

R¹, R² are each, independently of one another, H or Hal;

in Ie

R¹, R² are each, independently of one another, H or Hal,

A¹, A² are each, independently of one another, H or A;

in If

A¹, A² are each, independently of one another, H or A;

in Ig

R¹, R² are each, independently of one another, H or Hal,

A¹, A² are each, independently of one another, H or A,

A is alkyl having 1, 2, 3 or 4 C atoms,

Hal is F or Cl.

A base of the formula I can be converted with an acid into the relevantacid addition salt, for example by reacting equivalent amounts of thebase and the acid in an inert solvent such as ethanol and subsequentlyevaporating. Acids particularly suitable for this reaction are thosewhich provide physiologically acceptable salts. Thus, it is possible touse inorganic acids, for example sulfuric acid, nitric acid, hydrohalicacids such as hydrochloric acid or hydrobromic acid, phosphoric acidssuch as orthophosphoric acid, sulfamic acid, also organic acids, inparticular aliphatic, alicyclic, araliphatic, aromatic or heterocyclicmono- or polybasic carboxylic, sulfonic or sulfuric acids, for exampleformic acid, acetic acid, propionic acid, pivalic acid, diethylaceticacid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleicacid, lactic acid, tartaric acid, maleic acid, citric acid, gluconicacid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxy-ethanesulfonicacid, benzenesulfonic acid, p-toluene-sulfonic acid, naphthalenemono-and -disulfonic acids, lauryl sulfuric acid. Salts with physiologicallyunacceptable acids, for example picrates, can be used to isolate and/orpurify the compounds of the formula I.

The invention furthermore relates to pharmaceutical preparationscomprising at least one phosphodiesterase VII inhibitor of the formula Iand/or one of its physiologically acceptable salts and/or solvates forcontrolling allergic disorders, asthma, chronic bronchitis, atopicdermatitis, psoriasis and other skin disorders, inflammatory disorders,autoimmune diseases such as, for example, rheumatoid arthritis, multiplesclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis,osteoporosis, transplant rejection reactions, cachexia, tumour growth ortumour metastases, sepsis, memory disturbances, atherosclerosis andAIDS.

This preferably entails the substances being administered in dosagesbetween about 1 and 500 mg, in particular between 5 and 100 mg, perdosage unit. The daily dose is preferably between about 0.02 and 10mg/kg of body weight. The specific dose for each patient depends on awide variety of factors, however, for example on the efficacy of thespecific compound employed, on the age, body weight, general state ofhealth, sex, on the diet, on the time and route of administration, onthe rate of excretion, medicinal substance combination and severity ofthe particular disorder to which the therapy applies. Oraladministration is preferred.

The pharmaceutical preparations can be used as pharmaceuticals in humanor veterinary medicine. Suitable carriers are organic or inorganicsubstances which are suitable for enteral (for example oral), parenteralor topical administration and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatin, carbohydrates suchas lactose or starch, magnesium stearate, talc, petrolatum. Inparticular, tablets, pills, coated tablets, capsules, powders, granules,syrups, suspensions or drops are used for oral administration,suppositories for rectal administration, solutions, preferably oily oraqueous solutions, also suspensions, emulsions or implants, forparenteral administration, ointments, creams or dusting powders fortopical administration. The novel compounds can also be lyophilized, andthe resulting lyophilizates can be used, for example, to manufactureproducts for injection. The stated preparations can be sterilized and/orcomprise excipients such as lubricants, preservatives, stabilizersand/or wetting agents, emulsifiers, salts to influence the osmoticpressure, buffer substances, colouring agents, flavourings and/orseveral other active ingredients, for example one or more vitamins.

The invention particularly relates to the compounds of the formula Ilisted in the following examples, and their physiologically acceptablesalts and/or solvates as PDE VII inhibitors, and to the use thereof forproducing a pharmaceutical for controlling allergic disorders, asthma,chronic bronchitis, atopic dermatitis, psoriasis and other skindisorders, inflammatory disorders, autoimmune diseases such as, forexample, rheumatoid arthritis, multiple sclerosis, Crohn's disease,diabetes mellitus or ulcerative colitis, osteoporosis, transplantrejection reactions, cachexia, tumour growth or tumour metastases,sepsis, memory disturbances, atherosclerosis and AIDS.

EXAMPLES

5-[2-(2-Fluoro-4-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(2,4-Difluorophenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(3-Methylthiophenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(2,4-Dimethoxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-(2-Amino-2-phenylvinyl)-4-methylaminocarbonyl-3-phenylisoxazole,

5-(2-Phenylaminovinyl)-4-methoxycarbonyl-3-phenylisoxazole,

5-[2-(4-Carboxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(4-Carboxyphenylamino)vinyl]-4-methoxycarbonyl-3-phenylisoxazole,

5-[2-(5-Chloro-2-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(3,4-Dimethylphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-[2-(4-Chlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-(2-Phenylaminovinyl)-4-cyano-3-(2-chlorophenyl)isoxazole,

5-[2-(4-Methoxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-[2-(4-Carboxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-[2-(2-Fluoro-4-hydroxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-[2-(4-Fluorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-[2-(3,5-Dichlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-[2-(3-Chlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,

5-(2-Phenylaminovinyl)-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(4-Chlorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-(2-Phenylaminovinyl)-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(4-Chlorophenylamino)vinyl]-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(4-Carboxyphenylamino)vinyl]-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(2,4-Difluorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(2,4-Dichlorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(4-Carboxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(3,5-Dichlorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(4-Methoxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(2,4-Dimethoxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(2-Phenylphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-[2-(4-Methylphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,

5-(2-Phenylaminovinyl)-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole,

5-[2-(4-Carboxyphenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole,

5-[2-(4-Chlorophenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole,

5-[2-(3-Methoxyphenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole,

5-[2-(4-Chlorophenylamino)vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole,

5-(2-Phenylaminovinyl)-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole,

5-[2-(2,4-Dichlorophenylamino)vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole,

5-(2-Phenylaminovinyl)-4-cyano-3-phenylisoxazole,

5-[2-(3-Trifluoromethoxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(4-Methoxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(4-Methoxyphenylamino)vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole,

5-[2-(3-Methylthiophenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(2,4-Difluorophenylamino)vinyl]-4-cyano-3-phenylisoxazole,

5-[2-(2-Fluoro-4-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole.

The following examples relate to pharmaceutical preparations:

Example A Vials

A solution of 100 g of a phosphodiesterase VII inhibitor of the formulaI and 5 g of disodium hydrogen phosphate in 3 l of double-distilledwater is adjusted to pH 6.5 with 2 N hydrochloric acid, sterilized byfiltration, dispensed into vials, lyophilized under sterile conditionsand sealed sterile. Each vial comprises 5 mg of active ingredient.

Example B Suppositories

A mixture of 20 g of a phosphodiesterase VII inhibitor of the formula Iwith 100 g of soya lecithin and 1400 g of cocoa butter is melted, pouredinto moulds and left to cool. Each suppository comprises 20 mg of activeingredient.

Example C Solution

A solution is prepared from 1 g of a phosphodiesterase VII inhibitor ofthe formula I, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1g of benzalkonium chloride in 940 ml of double-distilled water. The pHis adjusted to 6.8, the volume is made up to 1 l, and the solution issterilized by irradiation. This solution can be used in the form of eyedrops.

Example D Ointment

500 mg of a phosphodiesterase VII inhibitor of the formula I are mixedwith 99.5 g of petrolatum under aseptic conditions.

Example E Tablets

A mixture of 1 kg of phosphodiesterase VII inhibitor of the formula I, 4kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg ofmagnesium stearate is compressed to tablets in a conventional way sothat each tablet comprises 10 mg of active ingredient.

Example F Coated Tablets

Tablets are compressed in analogy to Example E and are then coated in aconventional way with a coating of sucrose, potato starch, talc,tragacanth and colouring agent.

Example G Capsules

2 kg of phosphodiesterase VII inhibitor of the formula I are packed intohard gelatin capsules in a conventional way so that each capsulecomprises 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of phosphodiesterase VII inhibitor of the formula Iin 60 l of double-distilled water is sterilized by filtration, dispensedinto ampoules, lyophilized under sterile conditions and sealed sterile.Each ampoule comprises 10 mg of active ingredient.

Example I Spray for Inhalation

14 g of phosphodiesterase VII inhibitor of the formula I are dissolvedin 10 l of isotonic NaCl solution, and the solution is dispensed intocommercial spray vessels with a pump mechanism. This solution can besprayed into the mouth or nose. One spray actuation (about 0.1 ml)corresponds to a dose of about 0.14 mg.

What is claimed is:
 1. A compound of formula I

wherein R¹, R², R³, and R⁴ are each, independently of one another, Hal,OA¹, SA¹, A, H, COOA¹, CN or CONA¹A², R⁵ is COOA¹, CN or CONA¹A², A¹,and A² are each, independently of one another, H, A, alkenyl, cycloalkylor alkylenecycloalkyl, A is alkyl having 1 to 10 C atoms that isoptionally substituted by 1 to 7 F or Cl or F and Cl atoms, and Hal isF, Cl, Br or I, or a physiologically acceptable salt or solvate thereof.2. A pharmaceutical composition comprising a compound of formula Iaccording to claim 1 or a physiologically acceptable salt or solvatethereof and a pharmaceutically acceptable carrier.
 3. A method oftreating an allergic disorder, asthma, chronic bronchitis, atopicdermatitis, psoriasis, a skin disorder other than psoriasis, aninflammatory disorder, an autoimmune disease, rheumatoid arthritis,multiple sclerosis, Crohn's disease, diabetes mellitus, ulcerativecolitis, osteoporosis, a transplant rejection reaction, cachexia, atumor growth or a tumor metastases, sepsis, a memory disturbance,atherosclerosis or AIDS comprising administering an effective amount ofa pharmaceutical composition of claim 2 to a patient in need thereof. 4.A method of inhibiting phosphodiesterase VII comprising administering aneffective amount of a pharmaceutical composition of claim 2 to a patientin need thereof.
 5. A method of treating asthma comprising administeringan effective amount of a pharmaceutical composition of claim 2 to apatient in need thereof.
 6. A method of treating osteoporosis comprisingadministering an effective amount of a pharmaceutical composition ofclaim 2 to a patient in need thereof.
 7. A method of treating cachexiacomprising administering an effective amount of a pharmaceuticalcomposition of claim 2 to a patient in need thereof.
 8. A compoundaccording to claim 1 wherein A is methyl, ethyl, propyl. isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl,hexyl, trifluoromethyl or pentafluoroethyl, and wherein cycloalkyl has3-9 C atoms, and wherein alkenyl has 2-10 C atoms and is linear orbranched, and wherein alkylenecycloalkyl has 4-10 C atoms.
 9. A compoundaccording to claim 1 wherein cycloalkyl is cyclopentyl or cyclohexyl,and wherein alkenyl is preferably vinyl, propenyl or butenyl, andwherein alkylenecycloalkyl is methylenecyclopentyl, ethylenecyclopentyl,methylenecyclohexyl or ethylenecyclohexyl.
 10. A compound according toclaim 1, wherein R¹ is H.
 11. A compound according to claim 1, whereinR¹ and R² are H.
 12. A compound according to claim 1, wherein R¹ is Hand R² is F or Cl.
 13. A compound according to claim 1, wherein R¹ andR² are each, independently of one another, H or Hal.
 14. A compoundaccording to claim 1, wherein R¹ and R² are each, independently of oneanother, H or Hal, and A¹ and A² are each independently of one another,H or A.
 15. A compound according to claim 1, wherein A¹ and A² are each,independently of one another, H or A.
 16. A compound according to claim1, wherein R¹ and R² are each, independently of one another, H or Hal,A¹ and A² are each, independently of one another, H or A, A is alkylhaving 1, 2, 3 or 4 C atoms, and Hal is F or Cl.
 17. A compoundaccording to claim 1, wherein the compound of formula I is selected fromthe group consisting of5-[2-(2-Fluoro-4-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,5-[2-(2,4-Difluorophenylamino)vinyl]-4-cyano-3-phenylisoxazole,5-[2-(3-Methylthiophenylamino)vinyl]-4-cyano-3-phenylisoxazole,5-[2-(2,4-Dimethoxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,5-(2-Amino-2-phenylvinyl)-4-methylaminocarbonyl-3-phenylisoxazole,5-(2-Phenylaminovinyl)-4-methoxycarbonyl-3-phenylisoxazole,5-[2-(4-Carboxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,5-[2-(4-Carboxyphenylamino)vinyl]-4methoxycarbonyl-3-phenylisoxazole,5-[2-(5-Chloro-2-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,5-[2-(3,4-Dimethylphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,5-[2-(4-Chlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,5-(2-Phenylaminovinyl)-4-cyano-3-(2-chlorophenyl)isoxazole,5-[2-(4-Methoxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,5-[2-(4-Carboxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,5-[2-(2-Fluoro-4-hydroxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,5-[2-(4-Fluoropheoylamino)vinyl]-4-cyano-3-(2chlorophenyl)isoxazole,5-[2-(3,5-Dichlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,5-[2-(3-Chlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole,5-(2-Phenylaminovinyl)-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-[2-(4-Chlorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-(2-Phenylaminovinyl)-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole,5-[2-(4-Chlorophenylamino)vinyl]-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole,5-[2-(4-Carboxyphenylamino)vinyl]-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole,5-[2-(2,4-Difluorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-[2-(2,4-Dichlorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-[2-(4-Carboxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-[2-(3,5-Dichlorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-[2-(4-Methoxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-[2-(2,4-Dimethoxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-[2-(2-Phenylphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-[2-(4-Methylphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole,5-(2-Phenylaminovinyl)-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole,5-[2-(4-Carboxyphenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole,5-[2-(4-Chlorophenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole,5-[2-(3-Methoxyphenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole,5-[2-(4-Chlorophenylamino)vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole,5-(2-Phenylaminovinyl)-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole,5-[2-(2,4-Dichlorophenylamino)vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole,5-(2-Phenylaminovinyl)-4-cyano-3-phenylisoxazole,5-[2-(3-Trifluoromethoxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,5-[2-(4-Methoxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole,5-[2-(4-Methoxyphenylamino)vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole,5-[2-(3-Methylthiophenylamino)vinyl]-4-cyano-3-phenylisoxazole,5-[2-(2,4-Difluorophenylamino)vinyl]-4-cyano-3-phenylisoxazole, and5-[2-(2-Fluoro-4-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole.18. A method according to claim 3, wherein the patient is a human or ananimal.
 19. A method according to claim 3, wherein administration isoral administration.
 20. A method for antagonizing the production ofTNFα comprising administering an effective amount of a pharmaceuticalcomposition of claim 2 to a patient in need thereof.